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High-Risk Breast CancerPhase 2NCT00851110

Adjuvant Breast Cancer Study of the Netherlands Working Party for Autotransplantation in Solid Tumors

A Phase 2 study testing stem cell reinfusion and Chemotherapy in people with High-Risk Breast Cancer, run by University Medical Center Groningen at 10 sites in Netherlands.

Terminated

Stopped early. The study ended before it was planned to and will not resume.

Official record
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Trial summary

Objectives of the study: This randomized multicenter phase II study compares the tolerability, toxicity and quality of life between two high-dose chemotherapy regimens based on cyclophosphamide, thiotepa and carboplatin. Regimen A: full dose CTC. Regimen B: two courses of CTC (tCTC) with 33% dose reduction. Read more about this study

Who is it for?
Ages 18 to 50 years, women only
Conditions the study is for
High-Risk Breast Cancer
What is being tested?
stem cell reinfusion and Chemotherapy
Type of treatment
Surgery or procedure
How many people
50 participants
Where
10 sitesNetherlands
Study dates
Oct 2004to not given
Phase
Phase 2
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 50 years
  • Women only
  • No healthy volunteers
  • Adult

Who may be able to join

  • Modified radical mastectomy (or breast conserving surgery) and axillary clearance, histologically confirmed stage IIA, IIB or IIIA adenocarcinoma (excluding supraclavicular lymph nodes) of the breast, with 4 or more involved axillary lymph nodes. Presence of tumor cells near or in the resection margins at microscopic examination is acceptable
  • The primary tumor must be immunohistochemically negative for HER-2/neu expression. An immunohistochemistry score of 1+ is also acceptable. A score of 3+ is not acceptable. A score of 2+ is only acceptable if a FISH analysis (or equivalent) has clearly shown that there is no HER-2/neu gene-amplification
  • No prior chemotherapy or radiotherapy
  • No evidence of distant metastases
  • Age < 50 years
  • Performance status (ECOG-ZUBROD) 0 or 1;
Show all 13Show fewer
  • Normal bone marrow function, WBC > 4.0 x 109/l, platelets > 100 x 109/l;
  • Adequate renal function (creatinine clearance > 60 ml/min.);
  • Adequate hepatic function (serum bilirubin < 25 umol/l);
  • Study treatment must begin within 6 weeks of surgery;
  • No other malignancy except adequately treated in situ carcinoma of the cervix or basal cell carcinoma of the skin;
  • No significant prior or concomitant disorder that might interfere with adherence to the intensive treatment regimen, including but not limited to a history of angina, myocardial infarction or heart failure, severe lung function impairment, peptic ulcer disease, etc.;
  • Availability for follow-up.

Who cannot join

None listed.

Trial locations and contacts

10 sites in 1 country.

10 sites in 1 country

Netherlands10 sites

  • Free University Hospital

    Amsterdam, 1007 MB

  • The Netherlands Cancer Institute

    Amsterdam, 1066 CX

  • Academic Medical Center

    Amsterdam, 1105 AZ

  • Medisch Spectrum Twente

    Enschede, 7511 JX

  • University Medical Centre Groningen

    Groningen, 9713 GZ

  • Leiden University Medical Centre

    Leiden, 2333 JS

  • University Hospital Maastricht

    Maastricht, 6202 AZ

  • University Medical Centre Nijmegen St. Radboud

    Nijmegen, 6525 GA

  • Erasmus MC, Daniel den Hoed Cancer Center

    Rotterdam, 3075 EA

  • University Medical Centre Utrecht

    Utrecht, 3584 CX

Other trials in Netherlands

About this study

Official title: A Prospective Randomized Feasibility and Phase II Adjuvant Breast Cancer Study of the Netherlands Working Party for Autotransplantation in Solid Tumors.

Objectives of the study:

This randomized multicenter phase II study compares the tolerability, toxicity and quality of life between two high-dose chemotherapy regimens based on cyclophosphamide, thiotepa and carboplatin.

Read more

Regimen A: full dose CTC. Regimen B: two courses of CTC (tCTC) with 33% dose reduction.

Primary endpoints are:

  • Maximum degree of non-hematological toxicity.

Secondary endpoint:

  • Total number of hospital days.
  • Quality of life evaluations during and following high-dose chemotherapy (up to 1 year).
  • Effect of therapeutic dose monitoring of CTC or tCTC.

Trial design:

This investigation is a multicenter prospective randomized phase II study. Patients eligible for the study will be identified after mastectomy or wide tumor excision with axillary clearance. Following randomization, all patients will receive four courses of cyclophosphamide, epirubicin and fluorouracil (FEC). Patients with early progressive disease at any time will be taken off study. The first chemotherapy course must be given as soon as possible after the surgical procedure, preferably within 3 weeks, but not later than 6 weeks since primary surgery. After the third or fourth FEC course G-CSF is administered and peripheral stem cells will be harvested. All radiation therapy (including radiation therapy administered as part of a breast conserving strategy) must be postponed until all chemotherapy has been concluded.

Questionnaires, comprising the Rotterdam Symptom Checklist (RSCL) and the Short-Form General Health Survey (SF-36) will be sent by mail before randomization, after chemotherapy, 3 months thereafter, further on every l/2 yr till at least 1 year follow-up as performed earlier. [6, 28, 29].

All patients will be randomized before the initiation of chemotherapy.

  • The 'standard' treatment arm will include 4 courses of FEC followed by high-dose chemotherapy with a single course of full dose CTC followed by peripheral stem cell reinfusion. Subsequently, conventional external beam radiotherapy to the breast or chest wall and to the regional lymph node areas including the axilla and the parasternal area will be administered following guidelines of the individual center. Patients with hormone receptor positive disease will go on to receive 5 years of tamoxifen. Patients with receptor positive disease who have not entered menopause will be advised to undergo ovarian ablation as well.
  • The 'experimental' treatment arm will be identical to the 'standard' one, except that the single course of CTC will be replaced by 2 courses of tCTC each followed by peripheral stem cell reinfusion.
Read the detailed description

High-dose chemotherapy with the alkylating agent combination CTC appears to add significantly to the efficacy of conventional dose chemotherapy in patients with high-risk breast cancer, provided that the HER-2/neu gene is not amplified in the tumor. As a high-dose chemotherapy regimen, CTC is associated with significant toxicity [31,32]. Although high-dose alkylating therapy seems to be effective, there is virtually nothing known about the dose-response curve for this combination (for a detailed discussion see the classical paper by E. Frei III [32]. If one assumes that the efficacy increase levels off with increasing dose, the efficacy of tCTC might be almost as great as that of CTC, but with considerably less toxicity. In addition, two closely spaced courses of tCTC might further increase the efficacy of the regimen. There are some suggestions that a double transplant may be more effective than a single one, in multiple myeloma and in Ewing sarcoma. A similar suggestion has also been made for breast cancer (study of Nitz et al ref 4, table 1).

Being tested
stem cell reinfusion, Chemotherapy
Keywords
high dose, breast cancer, adjuvant
Medical subject headings
Breast Neoplasms

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • stem cell reinfusionProcedure or surgery

    hematopoietic stem cell reinfusion

  • ChemotherapyDrug

    High-dose chemotherapy consisting of cyclophosphamide, thiotepa and carboplatin

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Maximum degree of non-hematological toxicity.

Secondary outcomes (2)

  1. Total number of hospital days

  2. Quality of life evaluations during and following high-dose chemotherapy (up to 1 year)

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted25 Feb 2009 (estimated)
  2. Study startOct 2004

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
50 participants (estimated)
IDs, dates and publications
ClinicalTrials.gov ID
NCT00851110
Sponsor's protocol ID
METc 2004/110
Other IDs
CKTO 2005-15
Status last verified
Feb 2009
First submitted
23 Feb 2009
Last updated
25 Feb 2009
Results posted
No

Publications

  • Weiss RB, Rifkin RM, Stewart FM, Theriault RL, Williams LA, Herman AA, Beveridge RA. High-dose chemotherapy for high-risk primary breast cancer: an on-site review of the Bezwoda study. Lancet. 2000 Mar 18;355(9208):999-1003. doi: 10.1016/S0140-6736(00)90024-2.

    PubMed 10768448

  • Bergh J, Wiklund T, Erikstein B, Lidbrink E, Lindman H, Malmstrom P, Kellokumpu-Lehtinen P, Bengtsson NO, Soderlund G, Anker G, Wist E, Ottosson S, Salminen E, Ljungman P, Holte H, Nilsson J, Blomqvist C, Wilking N. Tailored fluorouracil, epirubicin, and cyclophosphamide compared with marrow-supported high-dose chemotherapy as adjuvant treatment for high-risk breast cancer: a randomised trial. Scandinavian Breast Group 9401 study. Lancet. 2000 Oct 21;356(9239):1384-91. doi: 10.1016/s0140-6736(00)02841-5.

    PubMed 11052580

  • Tallman MS, Gray R, Robert NJ, LeMaistre CF, Osborne CK, Vaughan WP, Gradishar WJ, Pisansky TM, Fetting J, Paietta E, Lazarus HM. Conventional adjuvant chemotherapy with or without high-dose chemotherapy and autologous stem-cell transplantation in high-risk breast cancer. N Engl J Med. 2003 Jul 3;349(1):17-26. doi: 10.1056/NEJMoa030684.

    PubMed 12840088

  • Nitz UA, Frick M, Mohrmann S. Lindemann H, Jackisch C, Werner C, Souchon R, Metzner B, Rufert U, Bender HG. Tandem high dose chemotherapy versus dose-dense conventional chemotherapy for patients with high risk breast cancer: Interim results from a multicenter phase III trial. Proc Am Soc Clin Oncol 22: 2003 (abstract 3344).

  • Bonneterre J, Roche H, Kerbrat P, Bremond A, Fumoleau P, Namer M, Goudier MJ, Schraub S, Fargeot P, Chapelle-Marcillac I. Epirubicin increases long-term survival in adjuvant chemotherapy of patients with poor-prognosis, node-positive, early breast cancer: 10-year follow-up results of the French Adjuvant Study Group 05 randomized trial. J Clin Oncol. 2005 Apr 20;23(12):2686-93. doi: 10.1200/JCO.2005.05.059.

    PubMed 15837983

  • Rodenhuis S, Bontenbal M, Beex LV, Wagstaff J, Richel DJ, Nooij MA, Voest EE, Hupperets P, van Tinteren H, Peterse HL, TenVergert EM, de Vries EG; Netherlands Working Party on Autologous Transplantation in Solid Tumors. High-dose chemotherapy with hematopoietic stem-cell rescue for high-risk breast cancer. N Engl J Med. 2003 Jul 3;349(1):7-16. doi: 10.1056/NEJMoa022794.

    PubMed 12840087

  • Peters WP, Rosner G, Vredenburgh J, Shpall EJ, Crump M, Marks L, Cirrincione C, Hurd D, Norton L, Ann B. Updated results of a prospective, randomized comparison of two doses of combination alkyating agents (AA) as consolidation after CAF in high-risk primary breast cancer involving ten or more axillary lymph nodes (LN): CALGB 9082/SWOG 9114/NCIC Ma-13. Proc ASCO 20:81, 2001

  • Gianni A, Bonadonna G. Five-Year Results of the randomized clinical trial comparing standard versus high-dose myeloablative chemotherapy in the adjuvant treatment of breast cancer with > 3 positive nodes (LN+). Proc ASCO 20: 80, 2001

  • Rodenhuis S, Westermann A, Holtkamp MJ, Nooijen WJ, Baars JW, van der Wall E, Slaper-Cortenbach IC, Schornagel JH. Feasibility of multiple courses of high-dose cyclophosphamide, thiotepa, and carboplatin for breast cancer or germ cell cancer. J Clin Oncol. 1996 May;14(5):1473-83. doi: 10.1200/JCO.1996.14.5.1473.

    PubMed 8622061

  • Rodenhuis S, de Wit R, de Mulder PH, Keizer HJ, Sleijfer DT, Lalisang RI, Bakker PJ, Mandjes I, Kooi M, de Vries EG. A multi-center prospective phase II study of high-dose chemotherapy in germ-cell cancer patients relapsing from complete remission. Ann Oncol. 1999 Dec;10(12):1467-73. doi: 10.1023/a:1008328012040.

    PubMed 10643538

  • Rodenhuis S, Demol J, Westermann A, Holtkamp MJ, Nooijen WJ, Slaper-Cortenbach ICM, Schornagel JH, Baars JW: The feasibility of three courses of 'tiny CTC' (tCTC) in patients with advanced breast cancer. in: KA Dicke and A Keating (Eds.) Autologous Marrow and Blood Transplantation. Proceedings of the Eighth International Symposium Arlington, Texas. Carden Jennings Publishing Company, Charlottesville, Virginia 1997. p 277-285

  • Schrama JG, Baars JW, Holtkamp MJ, Schornagel JH, Beijnen JH, Rodenhuis S. Phase II study of a multi-course high-dose chemotherapy regimen incorporating cyclophosphamide, thiotepa, and carboplatin in stage IV breast cancer. Bone Marrow Transplant. 2001 Jul;28(2):173-80. doi: 10.1038/sj.bmt.1703105.

    PubMed 11509935

  • Westermann AM, Holtkamp MM, Linthorst GA, van Leeuwen L, Willemse EJ, van Dijk WC, Nooijen WJ, Baars JW, Schornagel JH, Rodenhuis S. At home management of aplastic phase following high-dose chemotherapy with stem-cell rescue for hematological and non-hematological malignancies. Ann Oncol. 1999 May;10(5):511-7. doi: 10.1023/a:1026427724108.

    PubMed 10415999

  • van Warmerdam LJ, Rodenhuis S, van Tellingen O, Maes RA, Beijnen JH. Validation of a limited sampling model for carboplatin in a high-dose chemotherapy combination. Cancer Chemother Pharmacol. 1994;35(2):179-81. doi: 10.1007/BF00686644.

    PubMed 7987998

  • van Warmerdam LJ, Rodenhuis S, van der Wall E, Maes RA, Beijnen JH. Pharmacokinetics and pharmacodynamics of carboplatin administered in a high-dose combination regimen with thiotepa, cyclophosphamide and peripheral stem cell support. Br J Cancer. 1996 Apr;73(8):979-84. doi: 10.1038/bjc.1996.191.

    PubMed 8611435

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing stem cell reinfusion and Chemotherapy in people with High-Risk Breast Cancer, run by University Medical Center Groningen at 10 sites in Netherlands.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 13 inclusion and 0 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: stopped early, as of the sponsor's last update on 25 Feb 2009. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 10 sites in Netherlands. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study was stopped early. Results are not available in the source record.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Maximum degree of non-hematological toxicity.. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT00851110, which also lists 34 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 25 Feb 2009.

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